In vitro cytotoxicity and phototoxicity of N-piperazinyl quinolone derivatives with a 2-thienyl group.

We examined the cytotoxic potential of nine N-[2-substituted-2-(2-thienyl)ethyl] piperazinyl quinolone derivatives on human oral epithelial mouth carcinoma (KB) and human squamous carcinoma (A431) cell lines. Phototoxic properties of these compounds were also evaluated by mouse 3T3 fibroblast under ultraviolet-A (UVA) irradiation. The percent of cell viability was evaluated by MTT assay. Compound 6 having a 4-[2-(phenylmethoxyimino)-2-(2-thienyl)ethyl] group attached to N4 position of piperazine ring of enoxacin showed the highest cytotoxicity potential on both A431 and KB cell lines (IC50 of 3.11+/-0.52 and 4.91+/-1.94 microg/ml, respectively). While some of the other tested compounds exhibited clear phototoxic potential in 3T3 cell line, compound 6 showed only a minor potential of phototoxicity. These findings suggest the high potential of 4-[2-(phenylmethoxyimino)-2-(2-thienyl)ethyl] derivative of enoxacin as a cytotoxic compound with low potency of phototoxic reactions. The mentioned chemical was identified to be of special interest for further characterization.     

Antituberculosis agents. V. Synthesis,evaluation of in vitro antituberculosis activity and cytotoxicity of some 2-(5-nitro-2-furyl)-1,3,4-thiadiazole derivatives

A new series of 2-(5-nitro-2-furyl)-1,3,4-thiadiazole-2-sulfide, sulfoxide and sulfones were synthesized and evaluated for in vitro antituberculosis activity against Mycobacterium tuberculosis strain H37Rv using the radiometric BACTEC 460-TB methodology. Active compounds were also screened by serial dilution to assess toxicity to a VERO cell line. The results indicate that some compounds exhibited a good antituberculosis activity and the ethylthio analogue (5b) was the most active compound (MIC = 0.78 microg ml(-1)). Also, the cytotoxic effects indicate that compound 5b was the least toxic compound.     

Synthesis and in-vitro antimycobacterial activity of fluoroquinolone derivatives containing a coumarin moiety

A series of gatifloxacin, ciprofloxacin, and 8-OCH(3) ciprofloxacin coumarin derivatives with remarkable improvement in lipophilicity as compared to the parent fluoroquinolones was designed, synthesized, and characterized by (1) H-NMR, MS, and HRMS. These derivatives were evaluated for their in-vitro activity against Mycobacterium smegmatis CMCC 93202 and MTB H37Rv ATCC 27294. All of the synthesized compounds were less active than the parent compounds against M. smegmatis CMCC 93202, but the activity of compound 6 was found to be 2-8-fold more potent than ciprofloxacin, 8-OCH(3) ciprofloxacin, moxifloxacin, and rifampin, and comparable to gatifloxacin against MTB H37Rv ATCC 27294. These results indicated that the lipophilicity of the tested compounds is not the sole parameter affecting antimycobacterial activity.     

Antituberculosis agents VIII. Synthesis and in vitro antimycobacterial activity of alkyl alpha-[5-(5-nitro-2-thienyl)-1,3,4-thiadiazole-2-ylthio]acetates

A series of alkyl alpha-[5-(5-nitro-2-thienyl)-1,3,4-thiadiazole-2-ylthio]acetic acid esters 6a-e were synthesized and evaluated for in vitro antituberculosis activity against Mycobacterium tuberculosis strain H(37)Rv using the BACTEC 460 radiometric system and BACTEC 12B medium. The antituberculosis data indicated that methyl, propyl, buthyl and benzyl esters showed a significant in vitro antimycobacterium tuberculosis activity (MIC=0.39-0.78 microg/ml) and the ethyl analogue did not show a good activity (MIC>6.25 microg/ml, %inhibition=58). The most active compound of the series was n-propyl alpha-[5-(5-nitro-2-thienyl)-1,3,4-thiadiazole-2-ylthio]acetate (6c) with MIC value of 0.39 microg/ml.     

Antituberculosis agents, I: Synthesis and antituberculosis activity of 2-aryl-1,3,4-thiadiazole derivatives

The design, synthesis and antituberculosis activity of a series of 2-aryl-5-methylthio-1,3,4-thiadiazoles (5a-b), ethyl alpha-(5-aryl)-1,3,4-thiadiazole-2-ylthio)acetates (8a-b) and related compounds are described. All of the compounds were tested against Mycobacterium tuberculosis strain H37Rv in comparison to rifampicin. Six compounds exhibited a very good activity (MIC < 6.25 micrograms/ml, % Inhibition = 100).     

Antituberculosis agents II. Evaluation of in vitro antituberculosis activity and cytotoxicity of some 2-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazole derivatives

Using the radiometric BACTEC 460-TB methodology, the minimum inhibitory concentration (MIC) of a series of 2-(1-methyl-5-nitro-2-imidazolyl-1,3,4-thiadiazole-5-alkylsulfides, alkylsulfoxides and alkylsulfones which had been reported previously as antifungal agents, were determined. Active compounds were also screened by serial dilution to assess toxicity to a VERO cell line. The results indicate that compounds bearing a primary alkylthio substitution displayed good antituberculosis activity (MIC = 3.13-6.25 microg/ml). Oxidation to sulfone abolished the antituberculosis activity in methyl and propyl derivatives while the ethylsulfonyl analogue was active (MIC = 1.56 microg/ml). The cytotoxic effects indicate that 2-(1-methyl-5-nitro-2-imidazolyl)-5-methylthio-1,3,4-thiadiazole was the least toxic compound (IC50 > 10 microg/ml). Generally, all compounds showed a low selectivity index.     

含有取代吲哚满二酮-1-乙基的加替沙星衍生物的合成与抗结核作用研究

目的寻找具有优秀活性的喹诺酮类抗结核药物。方法设计合成脂溶性更大的含有取代吲哚满二酮-1-乙基的加替沙星衍生物,测定其体外抗分枝杆菌活性。结果共合成了14个新化合物,其结构经1H-NMR、MS和HRMS确证。目标物普遍具有良好的抗分枝杆菌活性(MIC为1.56~6.25μg/mL),但均弱于其母药加替沙星。其中,化合物3h对草分枝杆菌CMCC93201和耻垢分枝杆菌CMCC93202的活性分别是利福平的4倍和2倍。结论脂溶性并非决定喹诺酮类化合物抗分枝杆菌活性的唯一因素。     

In vitro antimicrobial and antimycobacterial activity of some chalcones and their derivatives

In this study, novel series of chalcone derivatives, namely, 4-[4-(3-phenyl-acryloyl)-phenylamino]-chromen-2-one (5a–k) have been synthesized from the intermediate 4-(4-acetyl-phenylamino)-chromen-2-one (4). Cyclization reaction of chalcone (5a–k) with hydrazine hydrate, guanidine nitrate, and malononitrile gives the corresponding 4-[4-(1-acetyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-phenylamino]-chromen-2-one (6a–k), 4-[4-(2-amino-6-phenyl-pyrimidin-4-yl)-phenylamino]-chromen-2-one (7a–k), and 2-amino-6-[4-(2-oxo-2H-chromen-4-ylamino)-phenyl]-4-phenyl-nicotinonitrile (8a–k) derivatives were synthesized. The newly synthesized compounds were evaluated for their antimycobacterial activity and antimicrobial activity against eight bacteria (S. aureus, B. cereus, E. coli, P. aeruginosa, K. pneumoniae, S. typhi, P. vulgaris, and S. flexneri) and four fungi (A. niger, C. albicans, A. fumigatus, and A. clavatus).     

Synthesis and antimycobacterial activity of some 2-pyridinecarboxyamidrazone derivatives.

A series of N1-aryliden-2-pyridincarboxyamidrazone derivatives was prepared. Some of the synthesized compounds showed interesting in vitro antimycobacterial activity against some strains of Mycobacterium and clinical isolates of Mycobacterium tuberculosis.     

Synthesis and antioxidant activity of flavanoid derivatives containing a 1,4-benzodioxane moiety

Flavanoids bearing a 1,4-benzodioxane moiety [rac-15a, -16a, -17, -18, (-)-15a, (-)-16a] were prepared from protocatechualdehyde (5) and tested for inhibitory activity on the superoxide anion (O2.-) release by human polymorphonuclear leukocytes (PMNLs).     

New ranitidine analogues containing the 2-aminobenzimidazole moiety: in vivo and in vitro histamine H2-receptor blocking activity

The paper reports the pharmacological profile of a new series of ranitidine analogues in which the diaminonitroethene group is replaced by the 2-amino-5(6)-substituted and unsubstituted benzimidazole moieties. These derivatives show a histamine H2-receptor blocking activity comparable to that of the model both in vitro (KB on atria 0.16-1.15 microM) and in vivo (ID50 on the perfused stomach of the anaesthetized rat from 0.34 to 4.10 mumol kg-1 i.v.). The results are consistent with the hypothesis that, at least in the ranitidine analogues, the "urea equivalent" moiety may be replaced by a polar group partially ionized at physiological pH without loss of H2-blocking activity.     

Synthesis and antibacterial activity of novel levofloxacin derivatives containing a substituted thienylethyl moiety

Background and the purpose of the study

Piperazinyl quinolones such as ciprofloxacin, ofloxacin and levofloxacin are an important group of quinolone antimicrobials which are widely used in the treatment of various infectious diseases. In the present study, we synthesized a new series of levofloxacin derivatives and evaluated their antibacterial activities.

Methods

The N-substituted analogs of levofloxacin 6a–j were prepared by nucleophilic reaction of N-desmethyl levofloxacin 11 with thienylethyl bromide derivatives 8 or 9. All target compounds were tested using conventional agar dilution method in comparison to levofloxacin and N-desmethyl levofloxacin and their MIC values were determined against a panel of Gram-positive and Gram-negative bacteria.

Results

All compounds showed significant antibacterial activities against Gram-positive bacteria (MIC = 0.04-6.25 μg/mL); however, the activity against Gram-negative bacteria was lower (MIC = 1.56–100 μg/mL). As is evident from the data, oxime derivatives 6e, 6h and 6i are superior in inhibiting the growth of Gram-positive bacteria (MIC = 0.04–0.19 μg/mL), and their activities were found to be 5–25 times better than N-desmethyl levofloxacin 11 and equal or better than levofloxacin 4.

Conclusion

We have designed and synthesized novel quinolone derivatives bearing functionalized thienylethyl moiety on the piperazine ring of levofloxacin. The results of antibacterial screening against Gram-positive and Gram-negative bacteria revealed that the introduction of functionalized thienylethyl moiety on the piperazine ring of levofloxacin can improve the activity against Gram-positive bacteria. Gram-positive bacteria are responsible for a wide range of infectious diseases, and rising resistance in this group is causing increasing concern. Thus, this study introduces structural features of levofloxacin scaffold for development of new candidates in the field of anti-Gram positive chemotherapy     

1,5-Diphenylpyrrole derivatives as antimycobacterial agents. Probing the influence on antimycobacterial activity of lipophilic substituents at the phenyl rings

Synthesis and biological evaluation of new derivatives of 1,5-bis(4-chlorophenyl)-2-methyl-3-(4-methylpiperazin-1-yl)methyl-1H-pyrrole (BM 212, 16) are reported. Variously substituted phenyl rings with different substitution pattern and lipophilicity were added to the pyrrole nucleus to evaluate their influence on the activity toward Mycobacterium tuberculosis (MTB) and atypical mycobacteria. The most active derivatives showed activity between 0.125-0.5 microg/mL (better than 16 and streptomycin) and protection index (64-256) higher than 16 (4) and similar to isoniazid and streptomycin (128).     

Synthesis and in vitro antitumor activities of xanthone derivatives containing 1,4-disubstituted-1,2,3-triazole moiety

To explore the more active antitumor compounds, two series of new xanthones, containing 1,4-disubstituted-1,2,3-triazole moiety were designed and synthesized. Eaton’s Reagent and “click reaction” were used in the synthesis. Most of the title compounds showed good inhibitory activity against the hepatoma carcinoma cell line (Bel-7402) and human cervical carcinoma cell line (HeLa) in vitro. Compounds 10a, 10e, 10f, 11r and 11t had potent activity with IC₅₀ values, ranging from 2.2 ± 0.17 to 7.1 ± 0.27 ∝M, which was equivalent to Doxorubicin.     

Synthesis and antimycobacterial activity of pyrazine and quinoxaline derivatives

A series of pyrazine and quinoxaline derivatives have been synthesized, and their activity against M. tuberculosis (Mtb) and Mycobacterium avium (MAC) are reported. The 4-acetoxybenzyl ester of pyrazinoic acid and 4'-acetoxybenzyl 2-quinoxalinecarboxylate showed excellent activity against Mtb (MIC ranges of less than 1-6.25 microg/mL) but only modest activity against MAC (MICs of 4-32 microg/mL).     

Antituberculosis agents. V: Alpha-[5-(5-nitro-2-furyl)-1,3,4-oxadiazol-2-ylthio]acethydrazide and related compounds

alpha-[5-(5-Nitro-2-furyl)-1,3,4-oxadiazol-2-ylthio]aceth ydrazide, alpha-[5-(5-nitro-2-furyl)-1,3,4-oxadiazol-2-ylthio]acetamid e, delta-allyl-1-[( 5-(5-nitro-2-furyl)-1,3,4-oxadiazol-2-ylthio]acety) thiosemicarbazide, and other related compounds have been synthesised for testing against Mycobacterium tuberculosis.     

Synthesis and in vitro aldose reductase inhibitory activity of compounds containing an N-acylglycine moiety

A number of N-benzoylglycines (6), N-acetyl-N-phenylglycines (7), N-benzoyl-N-phenylglycines (8), and tricyclic N-acetic acids (9-12) were synthesized as analogues of the N-acylglycine-containing aldose reductase inhibitors alrestatin and 2-oxoquinoline-1-acetic acid. Derivatives of 6, which represent ring-simplified analogues of alrestatin, are very weak inhibitors of aldose reductase obtained from rat lens, producing 50% inhibition only at concentrations exceeding 100 microM. Compounds of series 7 were designed as ring-opened analogues of the 2-oxoquinolines. While these derivatives are more potent than compounds of series 6 (IC50S of 6-80 microM), they are less active than the corresponding 2-oxoquinolines. Analogues of series 8 were designed as hybrid structures of both alrestatin and the 2-oxoquinoline-1-acetic acids. These compounds are substantially more potent than compounds of series 6 and 7 and display inhibitory activities comparable to or greater than alrestatin or the 2-oxoquinolines (IC50S of 0.1-10 microM). Of the rigid analogues of 8, the most potent derivative is benzoxindole (12) with an IC50 of 0.67 microM, suggesting that fusion of the two aromatic rings of 8 in a coplanar conformation may optimize affinity for aldose reductase in this series.